SCHEDULE - Scandinavian Heart Transplant Everolimus de Novo Study With Early Calcineurin Inhibitor (CNI) Avoidance

NCT ID: NCT01266148

Last Updated: 2015-06-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 115 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-11-30
• Study Completion Date: 2012-12-31

Brief Summary

A controlled, randomized, open-label, multicenter study evaluating if early initiation of everolimus and early elimination of cyclosporine in de novo heart transplant recipients can improve long-term renal function and slow down the progression of chronic allograft vasculopathy

Detailed Description

This was a prospective, multi-center, randomized, controlled, parallel group, open label study in de novo heart transplant recipients. Patients eligibility for randomization was assessed 5 days after heart transplant.. Patients fulfilling the inclusion and exclusion criteria were randomized to one of two treatment groups: either conventional treatment with Cyclosporine A (CsA), Mycophenolate mofetil (MMF), and corticosteroids (Group A), or low-dose CsA and everolimus, reduced dose MMF, and corticosteroids (Group B). After 7 to 11 weeks, CsA was discontinued in Group B, while the standard triple-drug immunosuppressive regimen was maintained in Group A.

Conditions

Renal Function and Chronic Allograft Vasculopathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Everolimus

Participants started immunosuppressive regimen consisting of low dose CsA, everolimus, MMF and CS. After week 11, the participants regimen consisted of everolimus, MMF and CS.

Group Type: EXPERIMENTAL

Cyclosporine

Intervention Type: DRUG

Cyclosporine (CsA) control group target blood level: 150-350 ng/mL (month 1-3); 100-250 ng/mL (month 4-6); 60-200 ng/mL (month 7-12); everolimus group target blood level: 75-175 ng/mL (month 1-3)

Mycophenolate mofetil

Intervention Type: DRUG

Mycophenolate mofetil (MMF) target dose for control group: 2000-3000 mg/day everolimus group target dose: 1500-2000 mg/day and 75-175 ng/mL after week 11

Corticosteroids

Intervention Type: DRUG

Corticosteroids (CS) initiated at 0.2-0.5 mg/kg/day. Tapered to no less than 0.1 mg/kg at Month 3 for control and everolimus groups.

Everolimus

Intervention Type: DRUG

Everolimus 0.75 mg twice a day as starting dose up to a target blood level: 3-6 ng/mL (7-11 weeks) and 6-10 ng/mL for remaining of study

Anti Thymocyte Globulin

Intervention Type: DRUG

Induction therapy, Anti Thymocyte Globulin (ATG): 1-2 mg/kg/day during 3-5 days for control and everolimus groups after transplant surgery and prior to randomization.

Control

Participants received an immunosuppressive regimen consisting of CsA, MMF and CS throughout the study.

Group Type: EXPERIMENTAL

Cyclosporine

Intervention Type: DRUG

Cyclosporine (CsA) control group target blood level: 150-350 ng/mL (month 1-3); 100-250 ng/mL (month 4-6); 60-200 ng/mL (month 7-12); everolimus group target blood level: 75-175 ng/mL (month 1-3)

Mycophenolate mofetil

Intervention Type: DRUG

Mycophenolate mofetil (MMF) target dose for control group: 2000-3000 mg/day everolimus group target dose: 1500-2000 mg/day and 75-175 ng/mL after week 11

Corticosteroids

Intervention Type: DRUG

Corticosteroids (CS) initiated at 0.2-0.5 mg/kg/day. Tapered to no less than 0.1 mg/kg at Month 3 for control and everolimus groups.

Anti Thymocyte Globulin

Intervention Type: DRUG

Induction therapy, Anti Thymocyte Globulin (ATG): 1-2 mg/kg/day during 3-5 days for control and everolimus groups after transplant surgery and prior to randomization.

Interventions

Cyclosporine

Cyclosporine (CsA) control group target blood level: 150-350 ng/mL (month 1-3); 100-250 ng/mL (month 4-6); 60-200 ng/mL (month 7-12); everolimus group target blood level: 75-175 ng/mL (month 1-3)

Intervention Type: DRUG

Mycophenolate mofetil

Mycophenolate mofetil (MMF) target dose for control group: 2000-3000 mg/day everolimus group target dose: 1500-2000 mg/day and 75-175 ng/mL after week 11

Intervention Type: DRUG

Corticosteroids

Corticosteroids (CS) initiated at 0.2-0.5 mg/kg/day. Tapered to no less than 0.1 mg/kg at Month 3 for control and everolimus groups.

Intervention Type: DRUG

Everolimus

Everolimus 0.75 mg twice a day as starting dose up to a target blood level: 3-6 ng/mL (7-11 weeks) and 6-10 ng/mL for remaining of study

Intervention Type: DRUG

Anti Thymocyte Globulin

Induction therapy, Anti Thymocyte Globulin (ATG): 1-2 mg/kg/day during 3-5 days for control and everolimus groups after transplant surgery and prior to randomization.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Recipients of multi-organ transplants or a previous transplant were excluded, as were those with a donor aged > 70 years, cold ischemia time >6 hours, patients with severe systemic infection, recipients of ABO incompatible transplants, patients with severe hypercholesterolemia (>350mg/dL) or hypertriglyceridemia (>750 mg/dL), patients with past (<5 years). In order to continue in the study after week 7-11 (period 1), patients had to complete first 7-11 weeks on randomized immunosuppression and none of the following criteria should be present: Ongoing rejection treatment or experience of one grade 3R rejection or two or more grade 2R rejections during first 7-11 weeks.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Århus N, , Denmark

Novartis Investigative Site

Copenhagen, , Denmark

Novartis Investigative Site

Oslo, , Norway

Novartis Investigative Site

Gothenburg, , Sweden

Novartis Investigative Site

Linköping, , Sweden

Novartis Investigative Site

Lund, , Sweden

Countries

Denmark; Norway; Sweden

References

Arora S, Andreassen AK, Karason K, Gustafsson F, Eiskjaer H, Botker HE, Radegran G, Gude E, Ioanes D, Solbu D, Dellgren G, Ueland T, Aukrust P, Gullestad L; SCHEDULE (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) Investigators. Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Heart Transplant Recipients. Circ Heart Fail. 2018 Sep;11(9):e004050. doi: 10.1161/CIRCHEARTFAILURE.117.004050.

Reference Type: DERIVED

PMID: 30354362 (View on PubMed)

Norum HM, Michelsen AE, Lekva T, Arora S, Otterdal K, Olsen MB, Kong XY, Gude E, Andreassen AK, Solbu D, Karason K, Dellgren G, Gullestad L, Aukrust P, Ueland T. Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression. Am J Transplant. 2019 Apr;19(4):1050-1060. doi: 10.1111/ajt.15141. Epub 2018 Nov 5.

Reference Type: DERIVED

PMID: 30312541 (View on PubMed)

Andreassen AK, Broch K, Eiskjaer H, Karason K, Gude E, Molbak D, Stueflotten W, Gullestad L; SCHEDULE (SCandinavian HEart transplant everolimus De-novo stUdy with earLy calcineurin inhibitors avoidancE) Investigators. Blood Pressure in De Novo Heart Transplant Recipients Treated With Everolimus Compared With a Cyclosporine-based Regimen: Results From the Randomized SCHEDULE Trial. Transplantation. 2019 Apr;103(4):781-788. doi: 10.1097/TP.0000000000002445.

Reference Type: DERIVED

PMID: 30211826 (View on PubMed)

Nelson LM, Andreassen AK, Andersson B, Gude E, Eiskjaer H, Radegran G, Dellgren G, Gullestad L, Gustafsson F. Effect of Calcineurin Inhibitor-Free, Everolimus-Based Immunosuppressive Regimen on Albuminuria and Glomerular Filtration Rate After Heart Transplantation. Transplantation. 2017 Nov;101(11):2793-2800. doi: 10.1097/TP.0000000000001706.

Reference Type: DERIVED

PMID: 28230646 (View on PubMed)

Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Radegran G, Gude E, Jansson K, Solbu D, Karason K, Arora S, Dellgren G, Gullestad L; SCHEDULE investigators. Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study. Am J Transplant. 2016 Apr;16(4):1238-47. doi: 10.1111/ajt.13588. Epub 2016 Jan 28.

Reference Type: DERIVED

PMID: 26820618 (View on PubMed)

Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Radegran G, Gude E, Jansson K, Solbu D, Sigurdardottir V, Arora S, Dellgren G, Gullestad L; SCHEDULE Investigators. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial. Am J Transplant. 2014 Aug;14(8):1828-38. doi: 10.1111/ajt.12809.

Reference Type: DERIVED

PMID: 25041227 (View on PubMed)

Other Identifiers

2009-013074-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CRAD001ANO02

Identifier Type: -

Identifier Source: org_study_id